The protein kinases represent a large family of proteins, which plays a central role of in the regulation of wide variety of cellular processes and maintaining control over cellular function as enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of protein. A partial, non-limiting, list of these kinases include: receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGFR), insulin-like growth factor receptor (IGFR), the nerve growth factor receptor, TrkB, Met, and the fibroblast growth factor receptor, FGFR-3; non-receptor tyrosine kinase such as Abl and the function kinase Bcr-Abl, Lck, Csk, Fes, Bmx, and Src; and serine/threonint kinases such as B-Raf, C-Raf, Sgk, MAP kinases (e.g., MKK4, MKK6, etc.) and SAPK2a, SAPK2b and SAPK3. The consequences of phosphorylation with PKs are staggering; cell growth, differentiation and proliferation. Furthermore, aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders, as well as diseases resulting from inappropriate activation of the immune and nerve systems. In view of the apparent link between PK-related cellular activities and wide variety of human disorders, a great deal of effort is being expended in an attempt to identify ways to modulate PK activity.
Some of this effort has involved biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (mutant ligands (Patent Document 1); soluble receptors and antibodies (Patent Document 2) and tyrosine kinase inhibitors (Patent Document 3.).
In addition to the above, attempts have been made to identify small molecules which act as PK inhibitors, For example, bis-monocyclic, bicyclic and heterocyclic aryl compounds (Patent Document 4), vinylene azaindole derivatives (Patent Document 5) have been described as tyrosine kinase inhibitors. However these compounds have limited utility because of toxicity, poor bioavailability, or less potency.
On the other hand, some of indolinone derivatives are reported as PK inhibitors (Patent Document 6). Especially, 4-phenyl- or 4-pyridyl indolinone derivatives (Patent Document 7), and 5-(thiazol-4-yl)indolin-2-one derivatives (Patent Document 8) are reported.
However these prior arts do not disclose derivatives with other five-membered heteroaryl groups or heteroalicyclic group at 5th, 6th, or 7th position on indolinone and indolin.    [Patent Document 1] U.S. Pat. No. 4,966,849    [Patent Document 2] WO94/10202 pamphlet    [Patent Document 3] WO92/21660 pamphlet    [Patent Document 4] WO92/20642 pamphlet    [Patent Document 5] WO94/14808 pamphlet    [Patent Document 6] U.S. Pat. No. 5,792,783    [Patent Document 7] WO02/02551 pamphlet    [Patent Document 8] WO2009/033033 pamphlet